Although the eurotropic human herpesviruses (HSV-1, HSV-2 and VZV) that cause acute retinal necrosis (ARN), a relatively rare but potentially blinding disease, are well known and well described and there are numerous reports documenting the clinical course of this disease in human patients, comparatively little is known about the pathogenesis of this disease. Although no animal model of disease has absolute fidelity to its human counterpart, judicious interpretation of results from studies using animal models of disease, such as the mouse model of ARN, may aid in understanding of the pathogenesis of human disease. In this model, following uniocular anterior chamber (AC) inoculation of HSV-1, virus infects the anterior segment of the injected eye and then spreads via synaptically connected neurons to the brain and finally to the optic nerve and retina of the uninoculated contralateral eye resulting in ARN. Replication of virus in the retina is absolutely required for retinal destruction;however, studies using this model support the idea that other factors contribute to and exacerbate retinal destruction in the uninoculated eye. Accordingly, the studies proposed in this application will continue to unravel the pathogenesis of HSV-1 infection in the retina of the uninoculated contralateral eye using both in vitro and in vivo approaches. Two specific aims are proposed for these studies. The first specific aim will test the hypothesis that TNF-1 and TNF-1 induced apoptosis are critical to the pathogenesis of ARN after uniocular anterior chamber injection of HSV-1 and dissect the pathways by which this occurs. The second specific aim will test the hypothesis that autophagy plays a role in the pathogenesis of disease in the uninoculated eye. In the short term, the studies proposed for this project will provide new information about how the eye responds to HSV-1 infection and the attendant damage from such infection. In the longer term, information from these studies may lead to more appropriate or to specifically targeted therapies to control infection by the neurotropic members of the human herpesvirus family in the eye and brain. These studies may also provide new information about more general mechanisms by which the retina responds to infection or to other non-viral retinal-damaging processes. PUBLIC HEALTH RELEVANCE: Although the neurotropic human herpesviruses (HSV-1, HSV-2 and VZV) that cause acute retinal necrosis (ARN), a relatively rare but potentially blinding disease, are well known and there are numerous reports documenting the clinical course of this disease in human patients, comparatively little is known about the pathogenesis of this disease. The mouse model of this disease in which virus injected into the anterior chamber of one eye travels via nerves to the brain and from the brain to infect the optic nerve and retina of the uninoculated eye mimics aspects of ARN observed in human patients. The studies proposed in this application will use cultured retinas and virus infected mice to decipher the pathogenesis of HSV-1 infection in uninjected eye. Although no animal model of disease has absolute fidelity to its human counterpart, judicious interpretation of results from studies using the mouse model of ARN may help us understand more about the pathogenesis of herpesvirus infections in human patients. This information may allow development of specifically targeted therapies but may also provide insight into mechanisms by which the retina responds to infection or to other non-infectious processes that result in retinal damage.